Method of administering bisphosphonates

ABSTRACT

Bisphosphonates, in particular more potent N-bisphosphonates such as zoledronic acid and derivatives, can be used with satisfactory results for prolonged inhibition of bone resorption in conditions of abnormally increased bone turnover, e.g. osteoporosis, by intermittent administration, wherein the periods between bisphosphonate administrations are longer than was previously considered appropriate, e.g. a dosing interval of at least about 6 months or less frequently.

[0001] This invention relates to bisphosphonates, in particular to thepharmaceutical use of bisphosphonates in the treatment of conditions ofabnormally increased bone turnover, such as osteoporosis.

[0002] Bisphosphonates are widely used to inhibit osteoclast activity ina variety of both benign and malignant diseases in which bone resorptionis increased. Thus bisphosphonates have recently become available forlong-term treatment of patients with Multiple Myeloma (MM). Thesepyrophosphate analogs not only reduce the occurrence of skeletal relatedevents but they also provide patients with clinical benefit and improvesurvival. Bisphosphonates are able to prevent bone resorption in vivo;the therapeutic efficacy of bisphosphonates has been demonstrated in thetreatment of Paget's disease of bone, tumour-induced hypercalcemia and,more recently, bone metastasis and multiple myeloma (MM) (for review seeFleisch H 1997 Bisphosphonates clinical. In Bisphosphonates in BoneDisease. From the Laboratory to the Patient. Eds: The ParthenonPublishing Group, New York/London pp 68-163). The mechanisms by whichbisphosphonates inhibit bone resorption are still poorly understood andseem to vary according to the bisphosphonates studied. Bisphosphonateshave been shown to bind strongly to the hydroxyapatite crystals of bone,to reduce bone turn-over and resorption, to decrease the levels ofhydroxyproline or alkaline phosphatase in the blood, and in addition toinhibit both the activation and the activity of osteoclasts.

[0003] In addition bisphosphonates have been proposed for use in thetreatment of osteoporosis. Thus for instance, as described in U.S. Pat.No. 4,812,304 (Procter & Gamble) a method has been proposed for treatingor preventing osteoporosis in humans comprising administering to asubject afflicted with or at risk to osteoporosis a bone cell activatingcompound and a bone resorption inhibiting polyphosphonate according to aregime consisting of one or more cycles, whereby each cycle consists of:(a) a bone activating period of from about 1 day to about 5 days duringwhich a bone cell activating amount of a bone cell activating compoundis administered to said subject; followed by (b) a bone resorptioninhibition period of from about 10 days to about 20 days during whichethane-1-hydroxy-1,1-diphosphonic acid, or a pharmaceutically acceptablesalt or ester thereof, is administered daily to said subject in anamount from about 0.25 mgP/kg/day to about 3.3 mgP/kg/day; followed by(c) a rest period of from about 70 days to about 180 days during whichthe subject receives neither a bone cell activating compound nor a boneresorption inhibiting polyphophonate.

[0004] Also, for example, U.S. Pat. No. 4,761,406 (Procter & Gamble)proposes a method for treating osteoporosis, in humans or lower animalsafflicted with or at risk of osteoporosis, comprising administering tosaid human or lower animal an effective amount of a bone resorptioninhibiting polyphosphonate according to the following schedule: (a) aperiod of from about 1 day to about 90 days during which said boneresorption inhibiting polyphosphonate is administered daily in a limitedamount, followed by (b) a rest period of from about 50 days to about 120days, and (c) repeating (a) and (b) two or more times where a netincrease in bone mass of said human or animal results.

[0005] Surprisingly we have now found that bisphosphonates, inparticular more potent nitrogen-containing bisphosphonates, can be usedfor prolonged inhibition of bone resorption in conditions of abnormallyincreased bone turnover by intermittent administration, wherein theperiods between bisphosphonate administrations are longer than waspreviously considered appropriate to achieve satisfactory treatment. Inparticular and contrary to expectation we have found that satisfactorytreatment results can be obtained even when the dosing intervals greatlyexceed the natural bone remodelling cycle.

[0006] Accordingly the present invention provides a method for thetreatment of conditions of abnormally increased bone turnover in apatient in need of such treatment which comprises intermittentlyadministering an effective amount of a bisphosphonate to the patient,wherein the period between administrations of bisphosphonate is at leastabout 6 months.

[0007] The invention further provides use of a bisphosphonate in thepreparation of a medicament for the treatment of conditions ofabnormally increased bone turnover in which the bisphosphonate isadministered intermittently and in which the period betweenadministrations of bisphosphonate is at least about 6 months.

[0008] Conditions of abnormally increased bone turnover which may betreated in accordance with the present invention include: treatment ofpostmenopausal osteoporosis, e.g. to reduce the risk of osteoporoticfractures; prevention of postmenopausal osteoporosis, e.g. prevention ofpostmenopausal bone loss; treatment or prevention of male osteoporosis;treatment or prevention of corticosteroid-induced osteoporosis and otherforms of bone loss secondary to or due to medication, e.g.diphenylhydantoin, thyroid hormone replacement therapy; treatment orprevention of bone loss associated with immobilisation and space flight;treatment or prevention of bone loss associated with rheumatoidarthritis, osteogenesis imperfecta, hyperthyroidism, anorexia nervosa,organ transplantation, joint prosthesis loosening, and other medicalconditions. For example, such other medical conditions may includetreatment or prevention of periarticular bone erosions in rheumatoidarthritis; treatment of osteoarthritis, e.g. prevention/treatment ofsubchondral osteosclerosis, subchondral bone cysts, osteophyteformation, and of osteoarthritic pain, e.g. by reduction inintra-osseous pressure; treatment or prevention of hypercalcemiaresulting from excessive bone resorption secondary tohyperparathyroidism, thyrotoxicosis, sarcoidosis or hypervitaminosis D.

[0009] Thus in the present description the terms “treatment” or “treat”refer to both prophylactic or preventative treatment as well as curativeor disease modifying treatment, including treatment of patients at riskof contracting the disease or suspected to have contracted the diseaseas well as patients who are ill or have been diagnosed as suffering froma disease or medical condition. In particularly preferred embodimentsthe invention may be used for the prophylactic treatment of osteoporosisand similar diseases. Thus for example, bisphosphonate may beadministered to individuals at risk of developing osteoporosis on aregular basis at dosing intervals of at least about 6 months, e.g.bisphosphnates may be administered routinely to postmenopausal women atdosing intervals of once every 6 months or less frequently, e.g.annually.

[0010] In accordance with the present invention the bisphosphonatedosing interval is at least about 6 months, e.g. once every 180 days, orless frequently, conveniently once a year, or at any interval inbetween, e.g. once every 7, 8, 9, 10, or 11 months. Dosing intervals ofgreater than once per year may be used, e.g. about once every 18 monthsor about once every 2 years, or even less frequently, e.g. a frequencyof up to about once every 3 years or less often.

[0011] The bisphosphonates used in the present invention are typicallythose which inhibit bone resorption. Such compounds characteristicallycontain two phosphonate groups attached to a single carbon atom, forminga “P-C-P” structure, e.g. in a compound of formula I

[0012] wherein

[0013] X is hydrogen, hydroxyl, amino, alkanoyl, or an amino group mono-or disubstituted by C₁-C₄ alkyl;

[0014] R is hydrogen or C₁-C₄ alkyl and

[0015] Rx is an optionally substituted hydrocarbyl group,

[0016] and pharmaceutically acceptable salts thereof or any hydratethereof.

[0017] Thus, for example, suitable bisphosphonates for use in theinvention may include the following compounds or a pharmaceuticallyacceptable salt thereof, or any hydrate thereof:3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g.pamidronate (APD);3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g.dimethyl-APD; 4-amino-1-bydroxybutane-1,1-diphosphonic acid (alendronicacid), e.g. alendronate; 1-hydroxy-ethidene-bisphosphonic acid, e.g.etidronate; 1-hydroxy-3-(methylpentylamino)-propylidene-bisphosphonicacid, (ibandronic acid), e.g. ibandronate;6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP;3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,e.g. methyl-pentyl-APD (=BM 21.0955);1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g. zoledronicacid; 1-hydroxy-2-(3--pyridyl)ethane-1,1-diphosphonic acid (risedronicacid), e.g. risedronate, including N-methyl pyridinium salts thereof,for example N-methyl pyridinium iodides such as NE-10244 or NE-10446;1-(4-chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid),e.g. tiludronate;3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g.EB 1053 (Leo); 1-(N-phenylaminothiocarbonyl)methane--1,1-diphosphonicacid, e.g. FR 78844 (Fujisawa);5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethylester, e.g. U-81581 (Upjohn);1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid,e.g. YM 529; and 1,1-dichloromethane-1,1-diphosphonic acid (clodronicacid), e.g. clodronate; YM175.

[0018] Preferred bisphosphonates for use in the present invention areN-bisphosphonates, i.e. compounds which in addition to thecharacteristic geminal bisphosphonates moiety (e.g. “P-C-P”) comprise anitrogen-containing side chain, e.g. a compound of formula I′

[0019] wherein

[0020] X is hydrogen, hydroxyl, amino, alkanoyl, or an amino group mono-or disubstituted by C₁-C₄ alkyl;

[0021] R is hydrogen or C₁-C₄ alkyl and

[0022] Rx′ is a side chain which contains an optionally substitutedamino group, or a nitrogen containing heterocycle (including aromaticnitrogen-containing heterocycles),

[0023] and pharmaceutically acceptable salts thereof or any hydratethereof.

[0024] Thus, for example, suitable N-bisphosphonates for use in theinvention may include the following compounds or a pharmaceuticallyacceptable salt thereof, or any hydrate thereof:3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g.pamidronate (APD);3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g.dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronicacid), e.g. alendronate;1-hydroxy-3-(methylpentylamino)-propylidene-bisphosphonic acid,ibandronic acid, e.g. ibandronate;6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP;3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,e.g. methyl-pentyl-APD (=BM 21.0955);1-hydroxy-2--(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g.zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid(risedronic acid), e.g. risedronate, including N-methyl pyridinium saltsthereof, for example N-methyl pyridinium iodides such as NE-10244 orNE-10446;3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1--diphosphonic acid, e.g.EB 1053 (Leo); 1-(N-phenylaminothiocarbonyl)methane-1,1-diphosphonicacid, e.g. FR 78844 (Fujisawa);5-benzoyl-3,4dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester,e.g. U-81581 (Upjohn); and1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid,e.g. YM 529.

[0025] In one embodiment a particularly preferred N-bisphosphonate foruse in the invention comprises a compound of Formula II

[0026] wherein

[0027] Het is an imidazole, oxazole, isoxazole, oxadiazole, thiazole,thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or benzimidazoleradical, which is optionally substituted by alkyl, alkoxy, halogen,hydroxyl, carboxyl, an amino group optionally substituted by alkyl oralkanoyl radicals or a benzyl radical optionally substituted by alkyl,nitro, amino or aminoalkyl;

[0028] A is a straight-chained or branched, saturated or unsaturatedhydrocarbon moiety containing from 1 to 8 carbon atoms;

[0029] X′ is a hydrogen atom, optionally substituted by alkanoyl, or anamino group optionally substituted by alkyl or alkanoyl radicals, and

[0030] R is a hydrogen atom or an alkyl radical,

[0031] and the pharmacologically acceptable salts thereof.

[0032] In a further embodiment a particularly preferred bisphosphonatefor use in the invention comprises a compound of Formula III

[0033] wherein

[0034] Het′ is a substituted or unsubstituted heteroaromaticfive-membered ring selected from the group consisting of imidazolyl,imidazolinyl, isoxazolyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl,triazolyl, oxadiazolyl and thiadiazolyl wherein said ring can be partlyhydrogenated and wherein said substituents are selected from at leastone of the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, phenyl,cyclohexyl, cyclohexylmethyl, halogen and amino and wherein two adjacentalkyl substituents of Het can together form a second ring;

[0035] Y is hydrogen or C₁-C₄ alkyl;

[0036] X″ is hydrogen, hydroxyl, amino, or an amino group substituted byC₁-C₄ alkyl, and

[0037] R is hydrogen or C₁-C₄ alkyl;

[0038] as well as the pharmacologically acceptable salts and isomersthereof.

[0039] In a yet further embodiment a particularly preferredbisphosphonate for use in the invention comprises a compound of FormulaIV

[0040] wherein

[0041] Het′″ is an imidazolyl, 2H-1,2,3-,1H-1,2,4- or4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl or thiadiazolyl radical which is unsubstituted or C-mono-ordi-substituted by lower alkyl, by lower alkoxy, by phenyl which may inturn be mnon- or disubstituted by lower alkyl, lower alkoxy and/orhalogen, by hydroxy, by di-lower alkylamino, by lower alkylthio and/orby halogen and is N-substituted at a substitutable N-atom by lower alkylor by phenyl-lower alkyl which may in turn be mono- or di-substituted inthe phenyl moiety by lower alkyl, lower alkoxy and/or halogen, and

[0042] R2 is hydrogen, hydroxy, amino, lower alkylthio or halogen, lowerradicals having up to and including 7 C-atoms,

[0043] or a pharmacologically acceptable salt thereof.

[0044] Examples of particularly preferred N-bisphophonates for use inthe invention are:

[0045] 2-(1-Methylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

[0046] 2-(1-Benzylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

[0047] 2-(1-Methylimidazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

[0048] 1- Amino-2-(1-methylimidazol-4-yl)ethane-1,1-diphosphonic acid;

[0049] 1- Amino-2-(1-benzylimidazol-4-yl)ethane-1,1-diphosphonic acid;

[0050] 2-(1-Methylimidazol-2-yl)ethane-1,1-diphosphonic acid;

[0051] 2-(1-Benzylimidazol-2-yl)ethane-1,1-diphosphonic acid;

[0052] 2-(Imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid;

[0053] 2-(Imidazol-1-yl)ethane-1,1-diphosphonic acid;

[0054] 2-(4H-1,2,4-triazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

[0055]2-(Thiazol-2-yl)ethane-1,1-diphosphonic acid;

[0056] 2-(Imidazol-2-yl)ethane-1,1-diphosphonic acid;

[0057] 2-(2-Methylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;

[0058] 2-(2-Phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;

[0059] 2-(4,5-Dimethylimidazol-1-yl)-1-hydroxyethane-1,1-diphosphonicacid, and

[0060] 2-(2-Methylimidazol-4(5)-yl)-1-hydroxyethane-1,1-diphosphonicacid,

[0061] and pharmacologically acceptable salts thereof.

[0062] The most preferred N-bisphosphonate for use in the invention is2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid)or a pharmacologically acceptable salt thereof.

[0063] Pharmacologically acceptable salts are preferably salts withbases, conveniently metal salts derived from groups Ia, Ib, IIa and IIbof the Periodic Table of the Elements, including alkali metal salts,e.g. potassium and especially sodium salts, or alkaline earth metalsalts, preferably calcium or magnesium salts, and also ammonium saltswith ammonia or organic amines.

[0064] Especially preferred pharmaceutically acceptable salts are thosewhere one, two, three or four, in particular one or two, of the acidichydrogens of the bisphosphonic acid are replaced by a pharmaceuticallyacceptable cation, in particular sodium, potassium or ammonium, in firstinstance sodium.

[0065] A very preferred group of pharmaceutically acceptable salts ischaracterized by having one acidic hydrogen and one pharmaceuticallyacceptable cation, especially sodium, in each of the phosphonic acidgroups.

[0066] The bisphosphonic acid derivatives specifically mentioned aboveare well known from the literature. This includes their manufacture (seee.g. EP-A-513760, pp. 13-48). For example,3-amino-1-hydroxypropane-1,1-diphosphonic acid is prepared as describede.g. in U.S. Pat. No. 3,962,432 as well as the disodium salt as in U.S.Pat. Nos. 4,639,338 and 4,711,880, and1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid is prepared asdescribed e.g. in U.S. Pat. No. 4,939,130.

[0067] The bisphosphonates (hereinafter referred to as the Agents of theInvention) may be used in the form of an isomer or of a mixture ofisomers where appropriate, typically as optical isomers such asenantiomers or diastereoisomers or geometric isomers, typicallycis-trans isomers. The optical isomers are obtained in the form of thepure antipodes and/or as racemates.

[0068] The Agents of the Invention can also be used in the form of theirhydrates or include other solvents used for their crystallisation.

[0069] The Agents of the Invention are preferably used in the form ofpharmaceutical compositions that contain a therapeutically effectiveamount of active ingredient optionally together with or in admixturewith inorganic or organic, solid or liquid, pharmaceutically acceptablecarriers which are suitable for administration.

[0070] The Agents of the Invention may be administered alone or incombination with other bone active drugs, either in fixed combinationsor separately both physically and in time, including hormones, such as asteroid hormone, e.g. an estrogen; a partial estrogen agonist, orestrogen-gestagen combination;, a calcitonin or an analogue orderivative thereof, e.g. salmon, eel or human calcitonin parathyroidhormone or analogues thereof, e.g. e.g. PTH (1-84), PTH (1-34), PTH(1-36), PTH (1-38), PTH (1-31)NH₂ or PTS 893; a SERM (Selective EstrogenReceptor Modulator) e.g. raloxifene, lasofoxifene, TSE424, FC1271,Tibolone (Livial®); vitamin D or an analog. Such additional bone activedrugs may be administered more frequently than the bisphosphonate.

[0071] The pharmaceutical compositions may be, for example, compositionsfor enteral, such as oral, rectal, aerosol inhalation or nasaladministration, compositions for parenteral, such as intravenous orsubcutaneous administration, or compositions for transdermaladministration (e.g. passive or iontophoretic).

[0072] Preferably, the pharmaceutical compositions are adapted to oralor parenteral (especially intravenous, subcutaneous, intramuscular, ortransdermal) administration. Intravenous and oral, first and foremostintravenous administration is considered to be of particular importance.Preferably the bisphosphonate active ingredient is in the form of aparenteral, most preferably an intravenous form.

[0073] The particular mode of administration and the dosage may beselected by the attending physician taking into account the particularsof the patient, especially age, weight, life style, activity level,hormonal status (e.g. post-menopausal) and bone mineral density asappropriate.

[0074] The dosage of the Agents of the Invention may depend on variousfactors, such as effectiveness and duration of action of the activeingredient, e.g. including the relative potency of the bisphosphonateused, mode of administration, warm-blooded species, and/or sex, age,weight and individual condition of the warm-blooded animal.

[0075] Normally the dosage is such that a single dose of thebisphosphonate active ingredient from 0.005-20 mg/kg, especially 0.01-10mg/kg, is administered to a warm-blooded animal weighing approximately75 kg.

[0076] “mg/kg” means mg drug per kg body weight of the mammal—includingman—to be treated.

[0077] The dose mentioned above is typically administered intermittentlywith a period of at least 6 months between doses. The period betweenbisphosphonate administrations may be longer, e.g. conveniently once peryear, once per 18 months or once every 2 years, or even longer, or anyperiod in between.

[0078] Formulations in single dose unit form contain preferably fromabout 1% to about 90%, and formulations not in single dose unit formcontain preferably from about 0.1% to about 20%, of the activeingredient. Single dose unit forms such as ampoules of infusion solutionor solid for preparation of infusion solution doses, capsules, tabletsor dragées contain e.g. from about 0.5 mg to about 500 mg of the activeingredient. It will be appreciated that the actual unit dose used willdepend upon the potency of the bisphosphonates, the dosing interval androute of administration amongst other things. Thus the size of the unitdose is typically lower for more potent bisphosphonates and greater thelonger the dosing interval. For example, for more potent,N-bisphosphonates such as zoledronic acid a unit dose of from about 1 upto about 10 mg may be used for parenteral, e.g. intravenous,administration. For example, also for more potent N-bisphosphonates aunit dose of from about 1 to about 5 mg may be used parenterally fordosing once every 6 months; whereas a dose of from about 2 up to about10 mg may be used for once a year parenteral dosing.

[0079] Unit doses may be administered as a single or divided dose, i.e.a dose in which the unit dose is divided into two or more equal orunequal parts and in which the parts are administered to the patient atthe same time, during overlapping time periods or at separate timepoints. When the unit dose is administered as a divided dose at separatetime points, the interval between the separate administrations of thedivided dose may be from hours, e.g. I hour, up to about 1 month(approximately 30 days). In accordance with the invention, the timeinterval between administration of the last part of the divided dose andadministration of the first part of the next, following divided dose isat least 6 months or longer, e.g. about 1 year.

[0080] Thus, for example, a 10 mg unit dose may be administered as twoequal 5 mg parts at an interval of about 1 week to about 1 month, e.g.about 2 weeks, between administration of the parts. Alternatively, forexample, a 5 mg unit dose may be administered as two unequal parts of 4mg and 1 mg (or 3 mg and 2 mg) at an interval of from 1 to 3 days to 1to 3 weeks, e.g. about 1 week, between administration of the parts.

[0081] Pharmaceutical preparations for enteral and parenteraladministration are, for example, those in dosage unit forms, such asdragées, tablets or capsules and also ampoules. They are prepared in amanner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilising processes. Forexample, pharmaceutical preparations for oral administration can beobtained by combining the active ingredient with solid carriers, whereappropriate granulating a resulting mixture, and processing the mixtureor granulate, if desired or necessary after the addition of suitableadjuncts, into tablets or dragée cores.

[0082] Suitable carriers are especially fillers, such as sugars, forexample lactose, saccharose, mannitol or sorbitol, cellulosepreparations, and also binders, such as starch pastes, using, forexample, corn, wheat, rice or potato starch, gelatin, tragacanth,methylcellulose and/or polyvinylpyrrolidone and, if desired,disintegrators, such as the above-mentioned starches, also carboxymethylstarch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a saltthereof, such as sodium alginate. Adjuncts are especiallyflow-regulating agents and lubricants, for example silicic acid, talc,stearic acid or salts thereof, such as magnesium or calcium stearate,and/or polyethylene glycol. Dragee cores are provided with suitablecoatings that may be resistant to gastric juices, there being used,inter alia, concentrated sugar solutions that optionally contain gumarabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titaniumdioxide, or lacquer solutions in suitable organic solvents or solventmixtures or, to produce coatings that are resistant to gastric juices,solutions of suitable cellulose preparations, such as acetylcellulosephthalate or hydroxypropylmethylcellulose phthalate. Colouringsubstances or pigments may be added to the tablets or dragee coatings,for example for the purpose of identification or to indicate differentdoses of active ingredient.

[0083] Other orally administrable pharmaceutical preparations aredry-filled capsules made of gelatin, and also soft, sealed capsules madeof gelatin and a plasticiser, such as glycerol or sorbitol. Thedry-filled capsules may contain the active ingredient in the form of agranulate, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and, where appropriate, stabilisers. In soft capsules theactive ingredient is preferably dissolved or suspended in suitableliquids, such as fatty oils, paraffin oil or liquid polyethyleneglycols, it being possible also for stabilisers to be added.

[0084] Parenteral formulations are especially injectable fluids that areeffective in various manners, such as, intramuscularly,intraperitoneally, intranasally, intradermally, subcutaneously orpreferably intravenously. Such fluids are preferably isotonic aqueoussolutions or suspensions which can be prepared before use, for examplefrom lyophilised preparations which contain the active ingredient aloneor together with a pharmaceutically acceptable carrier, or from solutionconcentrates. The pharmaceutical preparations may be sterilised and/orcontain adjuncts, for example preservatives, stabilisers, wetting agentsand/or emulsifiers, solubilisers, salts for regulating the osmoticpressure and/or buffers.

[0085] Suitable formulations for transdermal application include aneffective amount of the active ingredient with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. Characteristically,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the active ingredientto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

[0086] The following Examples illustrate the invention describedhereinbefore.

[0087] In the following Examples the term “active ingredient” is to beunderstood as being any one of the bisphosphonic acid derivativesmentioned above as being useful according to the present invention.

EXAMPLES Example 1

[0088] Capsules containing coated pellets of active ingredient, forexample, disodium pamidronate pentahydrate, as active ingredient: Corepellet: active ingredient (ground) 197.3 mg Microcrystalline cellulose 52.7 mg (Avicel ® PH 105) 250.0 mg + Inner coating: Cellulose HP-M 603 10.0 mg Polyethylene glycol  2.0 mg Talc  8.0 mg 270.0 mg + Gastricjuice-resistant outer coating: Eudragit ® L 30 D (solid)  90.0 mgTriethyl citrate  21.0 mg Antifoam ® AF  2.0 mg Water Talc  7.0 mg 390.0mg

[0089] A mixture of disodium pamidronate with Avicel® PH 105 ismoistened with water and kneaded, extruded and formed into spheres. Thedried pellets are then successively coated in the fluidized bed with aninner coating, consisting of cellulose HP-M 603, polyethylene glycol(PEG) 8000 and talc, and the aqueous gastric juice-resistant coat,consisting of Eudragit® L 30 D, triethyl citrate and Antifoam® AF. Thecoated pellets are powdered with talc and filled into capsules (capsulesize 0) by means of a commercial capsule filling machine, for exampleHöfliger and Karg.

Example 2

[0090] Monolith adhesive transdermal system, containing as activeingredient, for example,1-hydroxy-2-(imidazol-1-yl)-ethane-1,1-diphosphonic acid: Composition:polyisobutylene (PIB) 300  5.0 g (Oppanol B1, BASF) P1B 335000  3.0 g(Oppanol B10, BASF) P1B 1200000  9.0 g (Oppanol B100, BASF) hydrogenatedhydrocarbon resin  43.0 g (Escorez 5320, Exxon)1-dodecylazacycloheptan-2-one  20.0 g (Azone, Nelson Res., Irvine/CA)active ingredient  20.0 g Total 100.0 g

[0091] Preparation:

[0092] The above components are together dissolved in 150 g of specialboiling point petroleum fraction 100-125 by rolling on a roller gearbed. The solution is applied to a polyester film (Hostaphan, Kalle) bymeans of a spreading device using a 300 mm doctor blade, giving acoating of about 75 g/m². After drying (15 minutes at 60° C.), asilicone-treated polyester film (thickness 75 mm, Laufenberg) is appliedas the peel-off film. The finished systems are punched out in sizes inthe wanted form of from 5 to 30 cm² using a punching tool. The completesystems are sealed individually in sachets of aluminised paper.

Example 3

[0093] Vial containing 1.0 mg dry, lyophilized1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid (mixed sodiumsalts thereof). After dilution with 1 ml of water, a solution(concentration 1 mg/ml) for i.v. infusion is obtained. Composition:active ingredient (free diphosphonic acid) 1.0 mg mannitol 46.0 mgTrisodium citrate × 2 H₂O ca. 3.0 mg water 1 ml water for injection 1ml.

[0094] In 1 ml of water, the active ingredient is titrated withtrisodium citrate×2 H₂O to pH 6.0. Then, the mannitol is added and thesolution is lyophilized and the lyophilisate filled into a vial.

Example 4

[0095] Ampoule containing active ingredient, for instance disodiumpamidronate pentahydrate dissolved in water. The solution (concentration3 mg/ml) is for i.v. infusion after dilution. Composition: activeingredient 19.73 mg (

5.0 mg of anhydrous active ingredient) mannitol   250 mg water forinjection    5 ml.

Example 5

[0096] Treatment of Patients

[0097] “A Multinational, Randomized, Double-Blind, Placebo-Controlled,Parallel-Group, Dose-Ranging, Safety and Efficacy Trial With IntravenousBolus Injections of Zoledronate In the Treatment of PostmenopausalOsteoporosis”

[0098] This was a dose and dose regimen-finding 12 month trial of ivzoledronic acid in patients with postmenopausal osteoporosis. Threehundred and fifty one patients were randomized to six study arms.Patients who had recent exposure to bone active drugs, e.g.bisphosphonates, estrogen, calcitonin, raloxifene, or a history ofmetabolic bone diseases were excluded. All patients were evaluated atbaseline and in 3-monthly visits. Zoledronic acid or placebo wasadministered as a bolus iv injection into a peripheral vein over 5minutes at every visit.

[0099] Efficacy was ascertained by measurement of percent change frombaseline in bone mineral density (BMD) measured by dual energy X-rayabsorptiometry (DEXA) as compared to placebo, at 6, 9, and 12 months.

[0100] As a special safety measure trans-iliac bone biopsies wereobtained in a subset of patients from all study arms at 12 months, andX-rays of the thoracic and lumbar spine from all study participants wereevaluated at baseline and at 12 months for the occurrence of incidentvertebral fractures.

[0101] Additionally, the degree and duration of suppression ofbiochemical markers of bone turnover—parathyroid hormone (PTH), bonespecific alkaline phosphatase (BSAP), serum C-telopeptide (CTX), serumosteocalcin, urine N-telopeptide (NTX)/creatinine ratio, urinedeoxypyridinoline (d-pyd)/creatinine ratio, urine pyridinoline(pyd)/creatinine ratio—was obtained every 3 months and measured in acentral laboratory.

[0102] Study Arms

[0103] Placebo

[0104] 0.25 mg zoledronic acid every 3 months

[0105] 0.5 mg zoledronic acid every 3 months

[0106] 1.0 mg zoledronic acid every 3 months

[0107] 2.0 mg zoledronic acid every 6 months

[0108] 4.0 mg zoledronic acid every 12 months

[0109] The 12 month results showed that all treatment arms demonstrateda percent change from baseline in BMD significantly (p<0.001) greaterthan placebo and not dissimilar one from another. Summary of stepwisemultiple comparisons of the active doses of zoledronate versus placebofor percent change from baseline in bone mineral density of the lumbarspine; postero anterior (L1-L4) at 12 months Confirmatory analysis ITTpopulation Standard Lower 97.5% Step error of confidence Number Mostsignificant contrast Difference difference limit p-value 1 zoledronate 4× 0.25 mg - placebo 5.1 0.55 3.7 <0.001 2 zoledronate 4 × 0.5 mg -placebo 4.9 0.56 3.5 <0.001 3 zoledronate 1 × 4.0 mg - placebo 4.6 0.533.3 <0.001 4 zoledronate 4 × 1.0 mg - placebo 4.5 0.55 3.2 <0.001 5zoledronate 2 × 2.0 mg - placebo 4.2 0.57 3.1 <0.001

[0110] Bone mineral density increased compared to placebo at the spine,hip, distal radius, and “total body”. Suppression of biochemical markersof bone formation and bone resorption confirmed and supported the BMDresults, demonstrating suppression of bone turnover to thepre-menopausal level throughout the 6 and 12 month dosing intervals.

[0111] The BMD data indicate that zoledronic acid dose administration asinfrequent as every 6 or 12 months can safely result in a statisticallysignificant and medically relevant bone mass increase. It is believedthat these data further indicate that a continued preservation of newbone beyond one year, without additional dose administration, is likelyor that further bone mass increase is possible. It is also believed thatre-treatment in additional cycles of every 6 month, 12 month, or lessfrequent dose administration will lead to further BMD increase. Areduction of risk of osteoporotic fracture is expected to accompany thebone mass increases.

1. A method for the treatment of conditions of abnormally increased boneturnover in a patient in need of such treatment which comprisesintermittently administering an effective amount of a bisphosphonate tothe patient, wherein the period between administrations ofbisphosphonate is at least about 6 months.
 2. Use of a bisphosphonate inthe preparation of a medicament for the treatment of conditions ofabnormally increased bone turnover in which the bisphosphonate isadministered intermittently and in which the period betweenadministrations of bisphosphonate is at least about 6 months.
 3. Amethod according to claim 1 or a use according to claim 2, wherein theperiod between administrations of bisphosphonate is at least about oncea year.
 4. A method according to claim 1 or use according to claim 2, inwhich the bisphosphonate is an N-bisphosphonate or a pharmaceuticallyacceptable salt thereof, or any hydrate thereof.
 5. A method accordingto claim 1 or use according to claim 2, for the prophylactic treatmentof osteoporosis wherein the period between administrations ofbisphosphonate is about once per year or less frequent.
 6. A methodaccording to claim 1 or use according to claim 2, in which thebisphosphonate is 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonicacid, or a pharmaceutically acceptable salt thereof, or any hydratethereof.
 7. A method according to claim 1 or use according to claim 2,for the prophylactic treatment of osteoporosis wherein the periodbetween administrations of bisphosphonateis about once every 18 months,about once every two years or less frequently.
 8. A method according toclaim 1 or a use according to claim 2 wherein the bisphosphonates isadministered parenterally.
 9. A method according to claim 1 or useaccording to claim 3 wherein the bisphosphonates is administeredintravenously, subcutaneously, intramuscularly, or transdermally.
 10. Amethod according to claim 1 or a use according to claim 2 in which thebisphosphonate is selected from:3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g.pamidronate (APD);3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g.dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronicacid), e.g. Alendronic; 1-hydroxy-ethidene-bisphosphonic acid, e.g.etidronate; 1-hydroxy-3-(methylpentylamino)-propylidene-bisphosphonicacid, (ibandronic acid), e.g. ibandronate;6amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP;3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,e.g. methyl-pentyl-APD (=BM 21.0955);1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g. zoledronicacid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronicacid), e.g. risedronate, including N-methyl pyridinium salts thereof,for example N-methyl pyridinium iodides such as NE-10244 or NE-10446;1-(4chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid),e.g. tiludronate;3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1--diphosphonic acid, e.g.EB 1053 (Leo); 1-(N-phenylaminothiocarbonyl)methane-1,1-diphosphonicacid, e.g. FR 78844 (Fujisawa);5-benzoyl-3,4dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester,e.g. U-81581 (Upjohn);1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid,e.g. YM 529; and 1,1-dichloromethane--1,1-diphosphonic acid (clodronicacid), e.g. clodronate; YM175, or a pharmaceutically acceptable saltthereof, or any hydrate thereof.
 11. Use of an N-bisphosphonate or apharmaceutically acceptable salt thereof, or any hydrate thereof for thepreparation of a medicament for the treatment of conditions ofabnormally increased bone turnover wherein said medicament is adaptedfor parenteral administration in a unit dosage form which comprises fromabout 1 up to about 10 mg of N-bisphosphonate or a pharmaceuticallyacceptable salt thereof, or any hydrate thereof, wherein the periodbetween administrations of bisphosphonate is at least about 6 months.12. Use according to claim 11, wherein the unit dosage form comprisesfrom about 1 up to about 5 mg and the period between administrations ofbisphosphonate is about once every 6 months.
 13. Use according to claim11, wherein the unit dosage form comprises from about 2 up to about 10mg and the period between administrations of bisphosphonate is aboutonce a year.
 14. Use according to any one of claims 11 to 13, whereinthe bisphosphonate is 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonicacid, or a pharmaceutically acceptable salt thereof, or any hydratethereof.
 15. A kit for the treatment of conditions of abnormallyincreased bone turnover comprising at least one unit dosage form of anN-bisphosphonate or a pharmaceutically acceptable salt thereof, or anyhydrate thereof, wherein said unit dosage form is adapted for parenteraladministration and comprises from about 1 up to about 10 mg ofN-bisphosphonate or a pharmaceutically acceptable salt thereof, or anyhydrate thereof, together with instructions for administering separateunit doses at intervals of is at least about 6 months.
 16. A kitaccording to claim 15, wherein the unit dosage form comprises from about1 up to about 5 mg and the period between administrations ofbisphosphonate is about once every 6 months.
 17. A kit according toclaim 15, wherein the unit dosage form comprises from about 2 up toabout 10 mg and the period between administrations of bisphosphonate isabout once a year.
 18. A kit according to claim 15, wherein thebisphosphonate is 1-hydroxy-2- (imidazol-1--yl)ethane-1,1-diphosphonicacid, or a pharmaceutically acceptable salt thereof, or any hydratethereof.